Cellular abnormalities of blood vessels as targets in cancer

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Tumor blood vessels have multiple structural and functional abnormalities. They are unusually dynamic, and naturally undergo sprouting, proliferation, remodeling or regression. The vessels are irregularly shaped, tortuous, and lack the normal hierarchical arrangement of arterioles, capillaries and venules. Endothelial cells in tumors have abnormalities in gene expression, require growth factors for survival and have defective barrier function to plasma proteins. Pericytes on tumor vessels are also abnormal. Aberrant endothelial cells and pericytes generate defective basement membrane. Angiogenesis inhibitors can stop the growth of tumor vessels, prune existing vessels and normalize surviving vessels. Loss of endothelial cells is not necessarily accompanied by simultaneous loss of pericytes and surrounding basement membrane, which together can then provide a scaffold for regrowth of tumor vessels. Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.

Introduction

Despite convincing evidence that tumor growth is angiogenesis-dependent and that attacking the blood supply might induce tumor regression, knowledge of the abnormalities of tumor blood vessels that make this approach feasible is surprisingly limited. Tumor blood vessels, like normal ones, are composed of endothelial cells, mural cells (pericytes or smooth muscle cells) and basement membrane. All of these are abnormal in tumor blood vessels. Here, we review the current understanding of these abnormalities and their potential as therapeutic targets.

Just as the vasculature of each normal organ reflects the distinctive local conditions, blood vessels of tumors mirror their environment. The bizarre nature of tumors results in bizarre blood vessels. Tumor vessels are exceptionally variable in size, shape and branching pattern, and are not organized in the conventional hierarchy of arterioles, capillaries and venules (Figure 1a,b). However, the severity and types of vascular defects vary with the particular conditions within a tumor [1].

Most tumor models in animals use fast-growing tumor xenografts, often in ectopic locations [2]. By comparison, human cancer tends to be slower growing, and the location is determined by the natural history of the disease. Vascularity of tumors varies, tending to be greatest in regions of active growth, often at the periphery, and absent in regions of necrosis. Such regional differences in vascular density can complicate the interpretation of estimates of tumor vascularity, but tumors with a high microvascular density tend to be more aggressive and prone to metastases [3].

Section snippets

Endothelial cells

Tumors acquire their vasculature as they grow by secreting factors that stimulate the formation of new vessels. The dominant process of vessel growth is angiogenesis by sprouting of existing vessels 4., 5. (Figure 2a). Here, the balance between endothelial cell division and apoptosis shifts towards proliferation [5]. Growth of tumor vessels has many features in common with sprouting angiogenesis in wound healing and other conditions but, although the general regulatory mechanisms are likely to

Pericytes

Pericytes are key cells in vascular development, stabilization, maturation and remodeling 23., 24.. From both structural and functional studies, pericytes are known to be intimately associated with endothelial cells. Indeed, an important criterion in the identification of pericytes is their position, along with endothelial cells, within the vascular basement membrane. Pericytes are present on capillaries, postcapillary venules and collecting venules throughout the body. Nonetheless, pericytes

Vascular basement membrane

Vascular basement membrane is a self-assembled, supramolecular complex of proteins, glycoproteins and proteoglycans that tightly envelops endothelial cells and pericytes of blood vessels. Type IV collagen, laminin, fibronectin and heparan sulfate proteoglycan are among the main components [33••]. In tumors, defects in epithelial basement membrane are well documented features of invasion [34], but the vascular basement membrane has received less attention. Once thought to be incomplete or

Response of tumor vessels to angiogenesis inhibitors

From their name, angiogenesis inhibitors would be expected to block the growth of new vessels and perhaps stop tumor growth but not necessarily affect existing vessels or cause tumor shrinkage. However, inhibitors of VEGF signaling not only stop angiogenesis but also cause regression of some tumor vessels and may reduce tumor size 42., 43., 44.••, 45.•.

Inhibition of VEGF signaling causes robust and rapid changes in all components of the wall of tumor vessels (Figure 1c) [46]. Within 24 hours,

Conclusions

Tumor blood vessels have multiple abnormalities resulting from the bizarre environment in which they grow. Conventional vascular hierarchy, where arterioles connect to capillaries that connect to venules, is absent in tumors. Endothelial cells of tumor vessels do not form a tight barrier, and pericytes are loosely attached. The aberrant distribution of vascular basement membrane — created when vessels grow and left behind when they regress — provides a historical record of the dynamic nature of

Update

Most tumors have few or no functional lymphatic vessels, yet metastases to lymph nodes are common in some types of cancer. He et al. [54] report that growth of lymphatic vessels around tumors requires intact VEGFR-3 signaling but not the involvement of bone marrow progenitor cells. Few lymphatics are present around tumors in mice with heterozygous loss-of-function mutation of VEGF-C, and none are present when VEGFR-3 signaling is blocked. Isaka et al. [55] show that, even when present,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Supported in part by the US National Institutes of Health grants HL24136 and HL59157 from the National, Heart, Lung and Blood Institute and P50 CA90270 and CA82923 from the National Cancer Institute, and funding from AngelWorks Foundation and the Vascular Mapping Project (DMM).

Glossary

Angiogenesis inhibitors
Strictly speaking, these are agents that block the growth of new blood vessels. However, these agents can also cause regression of existing tumor vessels and normalize ones that do not regress.
Pericytes
Also known as mural cells or periendothelial cells, these cells are located in the wall of capillaries, venules and most tumor vessels. Pericytes and endothelial cells produce the vascular basement membrane that envelops them.
Vascular normalization
The tendency toward

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